Cyclohexylamine derivatives as subtype selective nmda receptor antagonists

ABSTRACT

Described are cyclobexylamine derivatives of Formula I, Formula II, or Formula III and their pharmaceutically acceptable salts thereof:                    
     The compounds are antagonists of NMDA receptor channel complexes useful for treating cerebral vascular disorders such as, for example, cerebral ischemia, cardiac arrest, stroke, and Parkinson&#39;s disease. The substituents are described in the specification.

This application is a §371 filing of PCT/US01/15349 filed May 14, 2001,which claims benefit of U.S. Provisional Application 60/208,703 filedJun. 1, 2000; the entire contents of each of which are herebyincorporated herein by reference.

FIELD OF THE INVENTION

The invention pertains to cyclohexylamine derivatives asN-Methyl-D-Aspartate Antagonists (NMDA).

BACKGROUND OF THE INVENTION

Over excitation of NMDA receptor channel complexes on postsynapticneurons following excessive release of glutamic acid from synaptosomesand glutamic acid from synaptosomes and glial cells result in a massivecalcium ion influx into the neuronal cells, which leads to their death.This is believed to occur under ischemic or hypoxic conditions such asstroke, hypoglycemic, cardiac arrest and physical trauma. An NMDAreceptor antagonist might be therapeutically useful because it mayminimize damage of the central nervous system (CNS) induced by ischemicor hypoxic conditions. The NMDA receptor channel complex consists of atleast three binding domains including glutamic acid (or NMDA)recognition site, channel blocking binding site, andstrychnine-insensitive glycine binding type. Physiologically, a blockadeof at least one of these sites terminates the channel opening of theNMDA receptor to prevent a calcium ion influx (Nagata R. et al., J. Med.Chem., 1994;37:3956-3968).

Excessive excitation by neurotransmitters may be responsible for theloss of neurons in cerebral vascular disorders such as cerebral ischemiaor cerebral infauxtion resulting in a range of conditions such asthromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia,cardiac arrest, status epilepticus, perinatal, asphyxia anoxia, such asfrom near drowning, pulmonary surgery and cerebral trauma, as well aslathyrism, Alzheimer's disease, and Huntington's disease. Suchconditions likewise suggest the use of agents that may act asantagonists in the receptors identified above may lead to treatment ofamyotrophic lateral sclerosis (ALS), schizophrenia, parkinsonism,epilepsy, anxiety, pain, and drug addiction (PCT/EPO 94/01492 havingpublication number WO 94/26747 published Nov. 24, 1994, Watjen et al.).

L-glutamic acid, L-aspartic acid, and a number of other closely relatedamino acids have the ability to activate neurons in the nervous systemand therefor the vast majority of excitatory neurons in the mammalianCNS. Interaction with glutamic acid mediated neurotransmission isconsidered a useful approach in the treatment of neurological andpsychiatric diseases (WO 94/26746, published Nov. 24, 1994, Jacobsen etal.).

Excitatory amino acid receptor antagonists that block NMDA receptors arerecognized for usefulness in the treatment of a variety of disorders.NMDA receptors are intimately involved in the phenomenon ofexcitotoxicity, which may be a critical determinant of outcome ofseveral neurological disorders. Disorders known to be responsive toblockade of the NMDA receptor include acute cerebral ischemia (stroke orcerebral trauma, for example), muscular spasm, convulsive disorders,neuropathic pain and anxiety, and may be a significant causal factor inchronic neurodegenerative disorders such as Parkinson's disease(Klockgether T., Turski L., Ann. Neurol., 1993;34:585-593); humanimmunodeficiency virus (HIV) related neuronal injury, amyotrophiclaterial sclerosis (ALS), Alzheimer's disease (Francis P. T., Sims N.R., Procter A. W., Bowen D. M., J. Neurochem., 1993;60(5):1589-1604);and Huntington's disease (see Lipton S., TINS, 1933;16(12):527-532;Lipton V, Rosenberg P. A., New Eng. J. Med., 1994;330(9):613-622; andBigge C. F., Biochem. Pharmacol., 1993;45:1547-1561, and referencescited therein). NMDA receptor antagonists may also be used to preventtolerance to opiate analgesia or to help control withdrawal symptomsfrom addictive drugs (European Patent Application 488,959A).

Many of the properties of native NMDA receptors are seen in recombinanthomomeric NR1 receptors. These properties are altered by the NR2subunits. Recombinant NMDA receptors expressed in Xenopus Oocytes havebeen studied by voltage-clamp recording, and has developmental andregional expression of the mRNAs encoding NMDA receptor subunits.Electrophysiological assays were utilized to characterize the actions ofcompounds at NMDA receptors expressed in Xenopus Oocytes. The compoundswere assayed at four subunit combinations at cloned rat NMDA receptors,corresponding to three putative NMDA receptor subtypes (Moriyoshi etal., Nature, 1991;354:31-37; Monyer et al., Science, 1992;256:1217-1221; Kutsuwada et al, Nature, 1992;358:36-41; Sugihara et al.,Biochem. Biophys Res. Commun., 1992;185:826-832).

Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) inNakanishi's lab in 1991 provided an initial view of the molecularstructure of the NMDA receptor (Moriyoshi, supra., 1991). There areseveral other structurally related subunits (NMDAR2A through NMDAR2D)that join NR1 in heteromeric assemblies to form the functional ionchannel complex of the receptor (Annu. Rev. Neurosci., 1994; 17:31-108).The molecular heterogeneity of NMDA receptors implies a future potentialfor agents with subtype selective pharmacology.

SUMMARY OF THE INVENTION

Described are cyclohexylamines derivatives of Formula I and theirpharmaceutically acceptable salts thereof

wherein:

Ar is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2heteroatoms selected from the group consisting of N, O, and S with from0 to 2 substituents for each; the substituents are from the groups F,Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃, OCH₂CH₂OH or N(CH₃)₂;

or entgegen or zusammen —CH(R₁)═CH(R₂)—,

E is hydrogen or OH;

d is an integer of from 0 to 2;

n is an integer from 1 to 6;

q is an integer from 0 to 6;

R₁ and R₂ are independently selected from the group consisting ofhydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, aralkyl, or N(R₄)(R₅)wherein R₄ and R₅ are independently selected from hydrogen, alkyl,aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, hydroxyalkyl, andthioalkyl;

R is hydrogen, alkyl, C(O)R₆, C(O)OR₆, C(O)NHR₆, H₂NC(O)-alkyl, aralkyl,cycloalkyl (3-7 carbon atoms) alkyl, hydroxyalkyl, aminoalkyl,amino(hydroxy)alkyl, carboxyalkyl, heteroaralkyl, alkenylalkyl, or OHwherein R₆ is alkyl or aralkyl;

X is independently selected from hydrogen or an electron withdrawinggroup;

Y is a hydrogen bond donor group; and

* denotes cis or trans or a mixture thereof.

The invention also relates to compounds of Formula II

or a pharmaceutically acceptable salt thereof wherein:

Ar is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2heteroatoms selected from the group consisting of N, O, and S with from0 to 2 substituents for each; the substituents are from the groups F,Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃, OCH₂CH₂OH, or N(CH₃)₂;

E is hydrogen or OH;

 d is an integer from 0 to 2;

t is an integer from 1 to 3;

R₁ and R₂ are independently selected from hydrogen, alkyl, OH,hydroxyalkyl, aminoalkyl, thioalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, guanidinyl, (aminocarbonyl)alkyl-, carboxyalkyl-,(methylthio)-alkyl-, or N(R₄)(R₅) wherein R₄ and R₅ are independentlyselected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl,ureidoalkyl, aminoalkyl, hydroxyalkyl, or thioalkyl;

R₃ is hydrogen, alkyl, OH, or aralkyl;

R is hydrogen, alkyl, C(O)R₆, C(O)OR₆, C(O)NHR₆, H₂NC(O)-alkyl, aralkyl,hydroxyalkyl, aminoalkyl, amino(hydroxy)alkyl, carboxyalkyl,heteroaralkyl, alkenylalkyl, or OH wherein R₆ is alkyl or aralkyl;

X is independently selected from hydrogen or an electron withdrawinggroup;

Y is a hydrogen bond donor group; and

* denotes cis or trans or a mixture thereof.

The invention is also concerned with a pharmaceutical composition usefulfor treating disorders responsive to the selective blockade ofN-methyl-D-aspartate receptor subtypes in a mammal, including a human,suffering therefrom which comprises a therapeutically effective amountof at least one compound of Formula I, or Formula II or Formula III, andthe pharmaceutically acceptable salts thereof. The composition is usefulfor treating optionally disorders such as stroke, cerebral ischemia,trauma, hypoglycemia, neurodegenerative disorders, anxiety, depression,migraine headache, convulsions, aminoglycoside antibiotic-inducedhearing loss, psychosis, glaucoma, CMV retinitis, opioid tolerance orwithdrawal, chronic pain, or urinary incontinence.

The invention is also concerned with a method of treating disordersresponsive to the selective blockade of the N-methyl-D-aspartatereceptor subtypes in a mammal, including a human, suffering therefromwhich comprises administering in unit dosage form, at least one compoundrepresented by Formulas I-III or their pharmaceutically acceptable saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of the present invention preferred are compounds ofFormula I or pharmaceutically acceptable salts thereof. Even morepreferred are those compounds of Formula I wherein:

X is independently selected from hydrogen or an electron withdrawinggroup selected from the group consisting of halogen, nitro, cyano,aminoalkyl, CF₃, C(O)CH₃, and haloalkyl; and

Y is a hydrogen bond donor group selected from the group consisting ofOH, heterocycle, which heterocycle is a carboxylic acid or an amideisostere, NH₂, SH, and NHR₇, wherein R₇ is alkyl, aralkyl, C(O)R₈,C(O)OR₈, C(O)NHR₈, SO₂R₈, or SO₂NHR₈, and R₈ is alkyl, aralkyl, or aryl.

More preferred are compounds of Formula I or pharmaceutically acceptablesalts thereof wherein:

Ar is unsubstituted or substituted phenyl;

E is hydrogen;

X is independently selected from hydrogen or an electron withdrawinggroup selected from the group consisting of halogen, nitro, cyano,aminoalkyl, CF₃, C(O)CH₃, and haloalkyl; and

Y is a hydrogen bond donor group selected from the group consisting ofOH, heterocycle, which heterocycle is a carboxylic acid or an amideisostere, NH₂, SH, and NHR₇, wherein R₇ is alkyl, aralkyl, C(O)R₈,C(O)OR₈, C(O)NHR₈, SO₂R₈, or SO₂NHR₈, and R₈ is alkyl, aralkyl, or aryl;and

* denotes trans.

Still more preferred are compounds of Formula I or pharmaceuticallyacceptable salts thereof wherein:

E is hydrogen;

Ar is unsubstituted or substituted phenyl;

Z is as defined above and further a group wherein:

Ar and the nitrogen atom in Formula I are separated by from 2 to 4atoms;

X is hydrogen or an electron withdrawing group selected from the groupconsisting of halogen, nitro, cyano, aminoalkyl, alkyl, CF₃, C(O)CH₃,and haloalkyl;

Y is a hydrogen bond donor group selected from the group consisting ofOH, heterocycle, which heterocycle is a carboxylic acid or an amideisostere, NH₂, SH, and NHR₇, wherein R₇ is alkyl, aralkyl, C(O)R₈,C(O)OR₈, C(O)NHR₈, SO₂R₈, or SO₂NHR₈, and R₈ is alkyl, aralkyl, or aryl;and

* denotes trans.

Still more preferred are compounds of Formula I or pharmaceuticallyacceptable salts thereof wherein:

Ar is unsubstituted or substituted phenyl;

E is hydrogen;

Y is OH;

 wherein m is an integer of from 1 to 3;

R is hydrogen, methyl, C(O)CH₃, alkenylalkyl, heteroaralkyl,H₂NC(O)alkyl, or (C₃-C₇ cycloalkyl)alkyl;

X is hydrogen; and

* denotes trans.

Most preferred is a compound selected from those listed below:

trans-4-[3-(4-Phenylcyclohexylamino)propyl]phenol;

cis-4-[(1S,2S)-1-Hydroxy-2-(4-phenylcyclohexylamino)propyl]phenol;

trans-4-[(1S,2S)-1-Hydroxy-2-(4-phenylcyclohexylamino)propyl]phenol;

trans-4-{2-[4-(4-Fluorophenyl)-4-hydroxycyclohexylamino]ethyl}phenol;

trans-4-{3-[Methyl(4-phenylcyclohexyl)amino]propyl}phenol;

trans4[2-(4-Phenylcyclohexylamino)ethyl]phenol;

trans-4-{2-[Methyl(4-phenylcyclohexyl)amino]ethyl}phenol;

trans-4-[4-(4-Phenylcyclohexylamino)butyl]phenol; and

trans-4-{4-[Methyl(4-phenylcyclohexyl)amino]butyl}phenol.

Preferred are compounds of Formula II or pharmaceutically acceptablesalts thereof wherein:

X is independently selected from hydrogen or an electron withdrawinggroup selected from the group consisting of halogen, nitro, cyano,aminoalkyl, CF₃, C(O)CH₃, and haloalkyl; and

Y is a hydrogen bond donor group selected from the group consisting ofOH, heterocycle, which heterocycle is a carboxylic acid or an amideisostere, NH₂, SH, and NHR₇, wherein R₇ is alkyl, aralkyl, C(O)R₈,C(O)OR₈, C(O)NHR₈, SO₂R₈, or SO₂NHR₈, and R₈ is alkyl, aralkyl, or aryl.

More preferred are compounds of Formula II or pharmaceuticallyacceptable salts thereof wherein:

E is hydrogen;

Ar is unsubstituted or substituted phenyl;

Y is a hydrogen bond donor group selected from the group consisting ofOH, heterocycle, which heterocycle is a carboxylic acid or an amideisostere, NH₂, SH, and NHR₇, wherein R₇ is alkyl, aralkyl, C(O)R₈,C(O)OR₈, C(O)NHR₈, SO₂R₈, or SO₂NHR₈, and R₈ is alkyl, aralkyl, or aryl;

X is independently selected from hydrogen or an electron withdrawinggroup selected from the group consisting of halogen, nitro, cyano,aminoalkyl, CF₃, C(O)CH₃, and haloalkyl; and

* denotes trans.

Still more preferred are compounds of Formula II or pharmaceuticallyacceptable salts thereof wherein:

E is hydrogen;

Ar is unsubstituted or substituted phenyl;

T is a group wherein Ar and the nitrogen atom bearing R are separated by3 or 4 atoms;

Y is a hydrogen bond donor group selected from the group consisting ofOH, heterocycle, which heterocycle is a carboxylic acid or an amideisostere, NH₂, SH, and NHR₇, wherein R₇ is alkyl, aralkyl, C(O)R₈,C(O)OR₈, C(O)NHR₈, SO₂R₈, or SO₂NHR₈, and R₈ is alkyl, aralkyl, or aryl;

X is independently selected from hydrogen or an electron withdrawinggroup selected from the group consisting of halogen, nitro, cyano, CF₃,C(O)CH₃, and haloalkyl; and

* denotes trans.

Still more preferred are compounds of Formula II or pharmaceuticallyacceptable salts thereof wherein:

Ar is unsubstituted or substituted phenyl;

E is hydrogen;

R is hydrogen, C(O)CH₃, H₂NC(O)alkyl, alkenylalkyl, methyl,heteroaralkyl, or cycloalkyl (3-7 carbon atoms) alkyl;

Y is OH;

X is hydrogen; and

* denotes trans.

Another preferred compound is that of Formula III

with the substituents Y, X, d, W, R₁, R₂, V, R, E, and Ar are asdescribed above for Formula I.

Other preferred compounds of Formulas I-III are those above where *denotes cis instead of trans.

The term “alkyl” means a straight or branched hydrocarbon radical havingfrom 1 to 12 carbon atoms unless otherwise specified, also known as aC₁-C₁₂ alkyl, and includes, for example, methyl, ethyl, 1-propyl and2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 1,1-dimethylethyl,1-pentyl, 2-pentyl, 3-pentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl,3-hexyl, 4-methyl-1-pentyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl,5-methyl-1-hexyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 6-methyl-1-heptyl,5,5-dimethylhexyl, 1-nonyl, 2-nonyl, 1-decyl, 2-decyl, 1-undecyl,2-undecyl, 1-dodecyl, and 5-dodecyl. Alkyl groups may be unsubstitutedor independently substituted by from 1 to 3 substituents selected fromF, Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃, OCH₂CH₂OH, or N(CH₃)₂.

Alkyl groups having two or more carbons may optionally contain 1 or 2sites of unsaturation, the groups being known as alkenyl groups orradicals. Illustrative examples of an alkenyl group or radical havingfrom 2 to 12 carbon atoms, also known as a C₂ to C₁₂ alkenyl, includeethenyl, 1-propenyl, 2-propenyl, 1-buten-1-yl, 2-buten-1-yl,1-penten-1-yl, 2-penten-1-yl, 1-penten-3-yl, 1-penten-5-yl,1-hexen-1-yl, 1-hexen-4-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-octen 3-yl,5-nonen-2-yl, 4-undecen-4-yl, and 5-dodecen-2-yl.

The term “aryl” means an aromatic carbocyclic ring having from 6 to 10carbon atoms. Illustrative examples of an aryl group or radical includephenyl, 1-naphthyl, and 2-naphthyl. Aryl groups may be unsubstituted orindependently substituted by from 1 to 3 substituents selected from F,Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃, OCH₂CH₂OH, or N(CH₃)₂. Phenylis not substituted in the 4-position with a hydrogen bond donor group Y.

The term “aralkyl” means an aryl-alkyl-group or radical wherein aryl andalkyl have the meanings as defined above. Illustrative examples of anarylalkyl group or radical include benzyl, 4-fluorophenylmethyl,2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 3-methyl-3-phenylpropyl,1-naphthylmethyl, 1-naphthylethyl, 3-(1-naphthyl)-propyl,4-(1-naphthyl)-butyl, 4-(2-naphthyl)-butyl, 4-phenylheptyl, and12-(2-hydroxyphenyl)-dodec-3-yl.

The terms “(C₃-C₇ cycloalkyl)alkyl” or “cycloalkyl (3-7 carbon atoms)alkyl” means an “alkyl” group (as described above) substituted thereonby a cycloalkyl group of from 3 to 7 carbon atoms as cyclopentyl,cyclopropyl, cyclohexyl, and cycloheptyl.

The term “heteroatom” means nitrogen, oxygen, or sulfur.

The term “heteroaryl” means an unsaturated monocyclic group or radicalof 5 or 6 atoms, an unsaturated fused bicyclic group or radical of from8 to 10 atoms, or an unsaturated fused tricyclic group or radical offrom 11 to 14 atoms, the cyclic groups having 1 or 2 heteroatomsindependently selected from O, N, or S. Illustrative examples ofmonocyclic heteroaryl include 2- or 3-thienyl, 2- or 3-furanyl, 1-, 2-,or 3-pyrrolyl, 1-, 2-, or 4-imidazolyl, 1-, 3-, or 4-pyrazolyl, 2-, 4-,or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isoxazolyl, 3-, 4-,or 5-isothiazolyl, 2-, 3-, or 4-pyridinyl, 3-or 4-pyridazinyl, 2- or3-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl. Illustrative examples ofbicyclic heteroaryl include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-,3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzofuran, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl, and 1-, 2-, 3-, 4-, 5-, 6-, or 7-benzimidazolyl.Illustrative examples of tricyclic heteroaryl include 1-, 2-, 3-, or4-dibenzofuranyl, 1-, 2-, 3-, or 4-dibenzothienyl, and 1-, 2-, 3-, 4-,5-, 6-, 7-, 8-, or 9-(1,2,3,4-tetrahydroacridinyl). All with the provisothat when Z in Formula I is attached via a heteroatom, Z is attached toa carbon atom of the heteroaryl group or radical. Heteroaryl groups maybe unsubstituted or independently substituted by from 1 to 3substituents selected from F, Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃,OCH₂CH₂OH, or N(CH₃)₂.

As used above, a fused bicyclic group or radical is a group wherein tworing systems share two and only two atoms.

As used above, a fused tricyclic group or radical is a group whereinthree ring systems share four and only four atoms.

The term “heteroaralkyl” means a heteroaryl-alkyl-group or radicalwherein heteroaryl and alkyl have the meanings as defined above.Illustrative examples of an heteroaralkyl group or radical include4-pyridyl-methyl, (4-fluoro-quinolin-2-yl)methyl,2-(isoxazol-3-yl)ethyl, and 12-(5-chlorothiophen-2-yl)-dodec-3-yl.

The term “halogen” means bromine, chlorine, fluorine, or iodine.

The term “aminoalkyl” means an H₂N-alkyl-group or radical wherein alkylhas the meaning as defined above, which is a substituted alkyl orradical containing from 1 to 3 substituents wherein at least onesubstituent is —NH₂.

The term “hydroxyalkyl” means an HO-alkyl-group or radical wherein alkylhas the meaning as defined above, which is a substituted alkyl group orradical containing from 1 to 3 substituents wherein at least onesubstituent is —OH.

The term “amino(hydroxy)alkyl” means an H₂N(HO)-alkyl-group or radicalwherein alkyl has the meaning as defined above, which is a substitutedalkyl group or radical containing from 2 or 3 substituents wherein atleast one substituent is OH and one substituent is —NH₂.

The term “(aminocarbonyl)alkyl” means an H₂NC(O)-alkyl-group or radicalwherein alkyl has the meaning as defined above, which is a substitutedalkyl group or radical containing from 1 to 3 substituents wherein atleast one substituent is —(O)C—NH₂.

The term “thioalkyl” means an HS-alkyl-group or radical wherein alkylhas the meaning as defined above, which is a substituted alkyl group orradical containing from 1 to 3 substituents wherein at least onesubstituent is —SH.

The term “(methylthio)-alkyl-” means a CH₃S-alkyl-group or radicalwherein alkyl has the meaning as defined above, which is a substitutedalkyl group or radical containing from 1 to 3 substituents wherein atleast one substituent is —SCH₃.

The term “carboxyalkyl” means an HO₂C-alkyl-group or radical whereinalkyl has the meaning as defined above, which is a substituted alkylgroup or radical containing from 1 to 3 substituents wherein at leastone substituent is —CO₂H.

The term “haloalkyl” means a halogen-alkyl-group or radical whereinhalogen and alkyl have the meanings as defined above, which is asubstituted alkyl group or radical containing from 1 to 3 substituentswherein at least one substituent is selected from F, Cl, Br, or I.

The term “ureidoalkyl” means an H₂N—(C═O)—NH-alkyl-group or radicalwherein alkyl has the meanings as defined above, which is a substitutedalkyl group or radical containing from 1 to 3 substituents wherein atleast one substituent is H₂N—(C═O)—NH—.

The term “electron withdrawing group” means a group or radical selectedfrom halogen, nitro, cyano, alkyl, CF₃, C(O)CH₃, P(O)(O—R₉)₂, SO₂—R₉,SO₂NHR₉, C(O)NR₉R_(9′) wherein R₉ is independently selected from C₁-C₆alkyl or unsubstituted or substituted phenyl, —(C═NH)—NH₂,—(C═NH)—O-alkyl, methoxymethyl, or haloalkyl, wherein the substituentsmay be F, Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃, OCH₂CH₂OH, orN(CH₃)₂.

The term “alkenylalkyl” means a (C₂-C₁₂ alkenyl)-(C₁-C₁₂ alkyl)-group orradical wherein alkenyl and alkyl have the meanings defined above.

The phrase “heterocycle, which heterocycle is a carboxylic acid or anamide isostere” means a 5- or 6-membered monocyclic ring containing from1 to 4 heteroatoms selected from N, O, and S and providing a hydrogenbond donor moiety selected from NH, OH, and SH. Illustrative examplesinclude the following structures:

See also Greenwood J. R., Vaccarella G., Cooper H. R., Allan R. D.,Johnston G. A. R., Internet Journal of Chemistry, 1998; 1 (Article 38,Chart 4). Additional examples are well-known to the skilled artisan.(See, for example, (i) Lipinski C. A., Annual Reports in MedicinalChemistry, 1986;21(Chapters 21 and 27); ii) Thornber C. W., Chem. Soc.Rev., 1979;8:563; (iii) Burger A., Progress in Drug Research,1991;37:288-371.)

The term “entgegen” means the stereoisomerism about a carbon-carbondouble bond wherein the highest ranking substituent on each carbon areon opposite sides, which substituent ranking is based on the sequencerules of the Cahn-Ingold-Prelog system (March J., supra., 1993:109,127and references cited therein).

The term “zusammen” means the stereoisomerism about a carbon-carbondouble bond wherein the highest ranking substituent on each carbon areon the same side, which substituent ranking is based on the sequencerules of the Cahn-Ingold-Prelog system (March J., Advanced OrganicChemistry, 4^(th) ed., New York: John Wiley & Sons, 1992;109, 127-133and references cited therein).

The term “cis” means the stereoisomerism about a carbon-carbon doublebond, a monocyclic ring, a fused bicyclic ring, or a bridged bicyclicring wherein the highest ranking substituent on each of the two carbonsof relevance are on the same side, which substituent ranking is based onthe sequence rules of the Cahn-Ingold-Prelog system (March, J., AdvancedOrganic Chemistry, 4^(th) ed., 1992, New York: John Wiley & Sons,1992:109, 127-133 and references cited therein).

The term “trans” means the stereoisomerism about a carbon-carbon doublebond, a monocyclic ring, a fused bicyclic ring, or a bridged bicyclicring wherein the highest ranking substituent on each of the two carbonsof relevance are on opposite sides, which substituent ranking is basedon the sequence rules of the Cahn-Ingold-Prelog system (March J.,supra., 1992; 109:127-133 and references cited therein).

The terms “cis” or “trans” refers to the relative stereochemistry of thegroups attached to the cyclohexyl rings of Formulas I or II at thecarbon atoms denoted by “*.”

The term “(X)_(d)” wherein d is an integer from 0 to 2 means the group Xis present 0 to 2 times on the phenylene to which it is attached, whichgroup is independently selected from hydrogen or an electron withdrawinggroup wherein the electron withdrawing group is as defined above unlessotherwise stated. The groups X can be the same or different.

The terms

wherein n is an integer of from 1 to 6 and q is an integer of from 0 to6 mean a chain of from 1 to 6 carbons or from 0 to 6 carbons,respectively, wherein each carbon is independently substituted, whichsubstituents are the groups R₁ and R₂, wherein R₁ and R₂ areindependently (R₁ and R₂ in each occurrence can be the same ordifferent) selected from the groups consisting of hydrogen, alkyl, OH,hydroxyalkyl, aminolkyl, aralkyl, or N(R₄)(R₅) wherein R₄ and R₅ areindependently selected from hydrogen, alkyl, aralkyl, heteroaryl,heteroaralkyl, aminoalkyl, hydroxyalkyl and thioalkyl, unless otherwisestated. The groups R₁ can be the same or different and the groups R₂ canbe the same or different.

For purposes of the syntheses of the compounds of the present invention,reactive functional groups present in starting materials, reactionintermediates, or reaction products may be protected during chemicalreactions using protecting groups which render the reactive functionalgroups substantially inert to the reaction conditions (see for example,Green T. W., Wuts P. G., Protective Groups in Organic Synthesis, 2nd ed.New York: John Wiley & Sons, 1991). Thus, for example, protecting groupssuch as the following may be utilized to protect suitable amino,hydroxyl, and other groups of related reactivity: carboxylic acylgroups, such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups,such as ethoxycarbonyl, t-butoxycarbonyl (BOC),β,β,β-trichloroethoxycarbonyl (TCEC), β-iodoethoxycarbonyl;aryloxycarbonyl groups, such as benzyloxycarbonyl,ρmethoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, suchas trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such astrityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,diphenylphosphinyl, ρtoluenesulfonyl, and benzyl may all be utilized.The protecting group may be removed, after completion of the syntheticreaction of interest, by procedures known to those skilled in the art.For example, a BOC group may be removed by acidolysis, a trityl group byhydrogenolysis, TBDMS by treatment with fluoride ions, and TCEC bytreatment with zinc.

It is to be appreciated that the compounds of Formulas I-III may havechiral centers in which case, all stereoisomers thereof both separatelyand as racemic and/or diastereoisomeric mixtures are included.

Some of the compounds of Formulas I-III are capable of further formingpharmaceutically acceptable acid-addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogen-phosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinates suberate, sebacate, fimarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, malate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M. et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19.

The acid addition salt of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge, supra., 1977).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formulas I-III or a correspondingpharmaceutically acceptable salt of a compound of Formulas I-III.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low-melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low-melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted, and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or, synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antagonists or as agents for the treatment ofdiseases, the compounds utilized in the pharmaceutical method of thisinvention are administered at the initial dosage of about 0.01 mg toabout 100 mg/kg daily. A daily dose range of about 0.01 mg to about 10mg/kg is preferred. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, the compound being employed. Determination of the proper dosagefor a particular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day, if desired.

Tablet Formulation Ingredient Amount (mg) Compound 1 25 Lactose 50Cornstarch (for mix) 10 Cornstarch (paste) 10 Magnesium stearate (1%) 5Total 100

Compound 1 lactose and cornstarch (for mix) are blended to uniformity.The cornstarch (for paste) is suspended in 200 mL of water and heatedwith stirring to form a paste. The paste is used to granulate the mixedpowders. The wet granules are passed through a No. 8 hand screen anddried at 80° C. The dry granules are lubricated with the 1% magnesiumstearate and pressed into a tablet. Such tablets can be administered toa human from one to four times a day for treatment of disease caused byover excitation of NMDA receptor channel complexes.

The compounds of the present invention can be prepared according to thevarious synthetic schemes that follow. Protecting groups may be usedwhen appropriate throughout many of the schemes. Although specificallynoted in certain schemes, the appropriate use and choice of protectinggroups is well-known by one skilled in the art, and is not limited tothe specific examples below. It is also understood that such groups notonly serve to protect chemically reactive sites, but also to enhancesolubility or otherwise change physical properties. A good generalreference for protecting group preparation and deprotection is“Protective Groups in Organic Synthesis” by Green, supra., 1991. Anumber of general reactions such as oxidations and reductions are notshown in detail but can be done by methods understood by one skilled inthe art. General transformations are well reviewed in “ComprehensiveOrganic Transformation” by Richard Larock, and the series “Compendium ofOrganic Synthetic Methods” published by Wiley-Interscience, 1989. Ingeneral, the starting materials were obtained from commercial sourcesunless otherwise indicated.

Preparation of Compounds

These compounds can be prepared following the procedures described inthe examples below.

General Methods

HCl salts were prepared by treatment of a MeOH solution of the aminewith excess HCl in Et₂O (1 M). The salts were isolated either byfiltration if they precipitated directly from the etherial solution, orby first removal of the solvent under reduced pressure, and thencrystallization (Et₂O/MeOH).

Purity was determined by reversed phase HPLC by the following methods:

Method A:

column: YMC J'Sphere C18, ODS-M80, 150×4.6 mm, 4μ;

solvent A: 0.1% H₃PO₄ in H₂O;

solvent B: 0.1% H₃PO₄ in CH₃CN;

gradient: 10-100% B over 15 minutes; flow: 1 mL minute⁻¹;

detection: 210 nm.

Method B:

column: YMC J'Sphere C18, ODS-M80, 150×4.6 mm, 4μ;

solvent A: 0.1% H₃PO₄ in H₂O;

solvent B: 0.1% H₃PO₄ in MeOH;

gradient: 10% to 100% B over 15 minutes; flow: 1 mL min⁻¹;

detection: 210 nm.

Preparation of trans-1-Amino-4-phenylcyclohexane 5

Step 1: To an ice-cold, stirred solution of 4-phenylcyclohexanone 1(25.0 g, 140 mmol) in THF (200 mL), under an N₂ atmosphere, was addedL-selectride (172 mL of a 1.0 M solution in THF, 170 mmol) dropwise over15 minutes. After 0.5 hours of stirring, the reaction mixture wasquenched by the careful addition of H₂O. The reaction mixture waspartitioned between EtOAc (800 mL) and 2N HCl (500 mL). The organiclayer was washed with saturated NaHCO₃ (500 mL), and saturated NaCl (500mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure.Purification by flash chromatography (alumina, THF) gave alcohol 2 (5.4g, 22%): ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.14 (m, 5H), 4.64-4.54 (m, 1H),2.65-2.51 (m, 1H), 2.09-1.82 (m, 4H), 1.79-1.58 (m, 4H).

Step 2: To an ice-cold, stirred solution of alcohol 2 (5.4 g, 31 mmol)in TBF (200 mL), under an N₂ atmosphere, was added Et₃N (6.5 mL, 47mmol) followed by methanesulfonyl chloride (2.9 mL, 37 mmol). After 1hour, the reaction mixture was partitioned between EtOAc (500 mL) and 2NHCl (500 mL). The organic layer was washed with H₂O (500 mL), saturatedNaHCO₃ (500 mL) and saturated NaCl, dried (Na₂SO₄), and filtered.Concentration under reduced pressure gave mesylate 3 (5.5 g, 70%), whichwas used without further purification: ¹H NMR (500 MHz, CDCl₃) δ7.31-7.18 (m, 5H), 5.06-5.03 (m, 1H), 3.03 (s, 3H), 2.65-2.54 (m, 1H),2.25-2.17 (m, 2H), 1.90-1.65 (m, 6H

Step 3: A mixture of 3 (5.5 g, 21 mmol), NaN₃ (3.1 g, 48 mmol), andtetrabutylammonium hydrogen sulfate (0.71 g, 2.1 mmol), in DMSO (35 mL)was heated at 40-45° C. for 60 hours. After cooling, the reactionmixture was partitioned between EtOAc and H₂O. The organic layer waswashed with saturated NaCl, dried (Na₂SO₄), and filtered. Concentrationunder reduced pressure gave azide 4 (4.1 g, 97%), which was used withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.09 (m, 5H),3.40-3.28 (m, 1H), 2.59-2.45 (m, 1H), 2.20-1.89 (m, 4H), 1.62-1.41 (m,4H).

Step 4: To a solution of 4 (4.1 g, 20 mmol) in MeOH (60 mL) was addedAcOH (1 mL) and 10% Pd/C (50% wet). The reaction mixture was shakenunder an atmosphere of hydrogen at 50 psi for 3 hours. The reactionmixture was then purged with N₂, filtered through Celite, andconcentrated under reduced pressure. Purification by flashchromatography (silica, 89:10:1 CH₂Cl₂:MeOH:NH₄OH) gave amine 5 (2.3 g,66%): mp 180-185° C.; IR (KBr); 3026, 2925, 2361, 2340 cm⁻¹; ¹H NMR (500MHz, CD₃OD) δ 7.25-7.07 (m, 5H), 2.73 (tt, J=13, 4 Hz, 1H), 2.48 (tt,J=13, 4 Hz, 1H), 1.99 (br d, J=13 Hz, 2H), 1.88 (br d, J=13 Hz, 2H),1.53 (dddd, J=13, 13, 13, 4 Hz, 2H), 1.30 (dddd, J=13, 13, 13, 4 Hz,2H); CI—MS (methane) (m/z): 176 [M+H]⁺; HPLC: method B, 12.44 minutes(99.9%).

Methylamine (5.7 mL of a 2.0 M in THF, 11.4 mmol) was added to asolution of 4-phenylcyclohexanone 1 (2.0 g, 11 mmol) in anhydrous THF(30 mL), and the mixture was stirred at room temperature for 4 hours.BH₃—SMe₂ 1.6 mL, 16 mmol) was added, and stirring was continuedovernight. After quenching the reaction with MeOH, the solvents wereremoved under reduced pressure. The crude solid was dissolved in MeOH(10 mL), HCl (15 mL of a 1.0 M solution in Et₂O, 15 mmol) was added, andthe mixture concentrated under reduced pressure. Purification by flashchromatography (silica, 9:1:0.1 CH₂Cl₂: MeOH:NH₄OH) gavetrans-1-(methylamino)-4-phenylcyclohexane 6 (0.80 g, 39%) as a whitesolid: ¹H NMR (300 MHz, CD₃ OD) δ 7.27-7.11 (m, 5H), 2.64 m, 1H), 2.51(obs m, 1H), 2.48 (s, 3H), 2.47 (s, 3H), 2.11 (br d, J=11 Hz, 2H), 1.93(br d, J=11 Hz, 2H), 1.59 (dddd, J=11, 11, 2, 2 Hz, 2H), 1.42 (dddd,J=11, 11, 2, 2 Hz, 2H).

EXAMPLE 1

(a) trans-3-(4-Hydroxy-phenyl)-N-(4-phenylcyclohexyl)propionamide

(b) trans4-[3-(4-Phenylcyclohexylamino)propyl]phenol

Step 1: A mixture of 3-(4-hydroxyphenyl)propionic acid 7 (0.48 g, 2.9mmol), amine 5 (0.50 g, 2.9 mmol), EDC (0.67 g, 3.5 mmol), and HOBT(0.39 g, 2.9 mmol) in DMF (5 mL) was stirred under an atmosphere ofnitrogen overnight. The reaction mixture was partitioned between H₂O (25mL) and EtOAc (50 mL). The organic layer was washed with H₂O, 3N HCl (25mL), H₂O (25 mL), and saturated NaCl (25 mL). After drying (Na₂SO₄),concentration under reduced pressure gave (a)trans-3-(4-hydroxyphenyl)-N-(4-phenylcyclohexyl)propionamide (0.65 g,69%) which was used without further purification: ¹H NMR (300 MHz,CD₃OD) δ 7.28-7.06 (m, 5H), 3.74-3.60 (m, 1H), 2.80 (t, J=4 Hz, 2H),2.51-2.36 (m, 3H), 1.97-1.82 (m, 4H), 1.67-1.51 (m, 2H), 1.40-1.21 (m,2H).

Step 2: To a suspension oftrans-3-(4-hydroxyphenyl)-N-(4-phenylcyclohexyl)propionamide (0.65 g,2.0 mmol) in toluene (5 mL), under a nitrogen atmosphere, was addedDIBAL-H (12.0 mL of a 1 M in toluene, 12 mmol) with stirring. Thereaction mixture was heated under reflux overnight. Additional DIBAL-H(12 mL of a 1.0 M solution in toluene, 12 mmol) was added, and heatingwas continued for a further 1.5 hours. The reaction mixture was cooledto room temperature and quenched by the slow addition of MeOH (50 mL).The mixture was heated at reflux for 15 minutes, cooled to roomtemperature, filtered, and concentrated under reduced pressure.Purification by flash chromatography (silica, 10% MeOH:CH₂Cl₂) then(silica, 89:10:1 CH₂Cl₂: MeOH:NH₄OH) gave (b) trans4-[3-(4-phenylcyclohexylamino)propyl]phenol (110 mg) as a tan solid: mp211-214° C.; IR (KBr): 2926, 1516, cm⁻¹; ¹H NMR (300 MHz, CD₃OD) δ7.23-7.10 (m, 5H), 7.02 (d, J=8 Hz, 2H), 6.69 (d, J=8 Hz, 2H), 2.68-2.44(m, 6H), 2.04 (br d, J=13 Hz, 2H), 1.88 (br d, J=13 Hz, 2H), 1.82-1.73(m, 2H), 1.57 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.26 (dddd, J=13, 13, 13,3 Hz, 2H); CI—MS (methane) (m/z): 310 [M+H]⁺; HRMS-API (m/z): [M+H]⁺calculated for C₂₁H₂₇NO, 310.2171; found, 310.2166; HPLC: method A, 7.93minutes (95.2%); method B, 14.29 minutes (97.3%); Anal. Calcd. forC₂₁H₂₇NO.0.80H₂O: C, 77.88; H, 8.90; N, 4.32. Found: C, 77.52; H, 8.66;N, 4.12.

EXAMPLE 2

(a) trans 4-[(1S,2S)-1-Hydroxy-2-(4-phenylcyclohexylamino)propyl]phenol

(b) cis-4-[(1S,2S)-1-Hydroxy-2-(4-phenylcyclohexylamino)propyl]phenol

To a solution of ketone 1 (0.860 g, 4.90 mmol) and triethylamine (0.680mL, 4.90 mmol) in MeOH (10 mL) was added sodium sulfate (1.0 g) andamine 8 (1.00 g, 4.90 mmol). The reaction mixture was stirred for 2hours. After cooling to −78° C., sodium borohydride (62.0 mg, 1.63 mmol)was added. The reaction mixture was allowed to warm to room temperatureand then stirred overnight. The solvents were evaporated, and theresidue was passed through a plug of silica (eluent 1:4 MeOH:CH₂Cl₂).The filtrate was concentrated and the residue purified by flashchromatography (silica, 89:10:1 CH₂Cl₂:MeOH: NH₄OH) to give (b)cis-4-[(1S,2S)-1-hydroxy-2-(4-phenyl-cyclohexylamino)-propyl]phenol(0.168 g, 5%): mp 199-212° C.; IR (KBr): 3194, 2922, 2853, 1515 cm⁻¹; ¹HNMR (500 MHz, DMSO-d₆) δ 9.22 (b s, 1H), 7.25 (dd, J=8, 8 Hz, 2H),7.15-7.13 (m, 3H), 7.00 (d, J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 4.97 (bs, 1H), 4.24 (b s, 1H), 2.91 (b s, 1H), 2.66 (m, 1H), 2.37 (m, 1H),1.67-1.50 (m, 4H), 1.44-1.23(m, 4H), 1.07 (b s, 1H), 0.95 (d, J=6 Hz,3H); CI—MS (methane)(m/z); 326 [M+H]⁺; HPLC; method A, 7.49 minutes(96.1%) method B, 13.68 minutes (95.7%); Anal. Calcd forC₂₁H₂₇NO₂.0.25H₂O: C, 76.44; H, 8.40; N, 4.25. Found: C, 76.33; H, 8.46;N, 4.11; and (a)trans-4-[(1S,2S)-1-hydroxy-2-(4-phenylcyclohexylamino)propyl]phenol: mp233-235° C.; IR (KBr): 3289, 2939, 2861, 1514 cm⁻¹; ¹H NMR (500 MHz,CD₃OD) δ 7.29-7.15 (m, 7H), 6.81 (d, J=9 Hz, 2H), 5.03 (d, J=3 Hz, 1H),3.56-3.54 (m, 1H), 3.38-3.35 (m, 1H), 2.58 (t, J=11 Hz, 1H), 2.32-2.27(m, 2H), 2.03 (d, J=10 Hz, 2H), 1.69-1.61 (m, 4H), 1.11 (d, J=7 Hz, 3H);CI—MS (methane) (m/z): 326 [M+H]⁺; HPLC: method A, 7.69 minutes (97.8%);method B, 14.00 minutes (97.0%); Anal Calcd for C₂₁H₂₇NO₂.0.25H₂O.HCl:C, 68.84; H, 7.84; N, 3.82. Found: C, 68.64; H, 7.47; N, 3.67.

EXAMPLE 3

Preparation of4-{2-[4-(4-Fluorophenyl)-4-hydroxycyclohexylamino]ethyl}phenol

Step 1: A solution of ketal 9 (10.1 g, 64.7 mmol) in anhydrous THF (50mL) was cooled to −78° C. 4-Fluorophenylmagnesium bromide (78 mL of a1.0 M solution in THF, 78 mmol) was added, slowly over 10 minutes. After20 minutes, saturated NH₄Cl (10 mL) was added, and the mixture wasallowed to warm to room temperature. The mixture was partitioned betweenCHCl₃ and saturated NH₄Cl. The organic layer was dried (Na₂SO₄),filtered through Celite, and concentrated under reduced pressure.Purification by flash chromatography (silica gel, 1:9 to 3:7EtOAc:hexanes, loaded in a minimum of CH₂Cl₂) gave 10 (10.9 g, 67%), asa white solid: mp 35-39° C.; IR (KBr): 2935, 1713, 1510 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 7.50 (dd, J=8, 8 Hz, 2H), 7.05 (dd, J=8, 8 Hz, 2H),4.00-3.91 (m, 5H), 2.25-2.08 (m, 4H), 1.85 (d, J=8 Hz, 2H), 1.65 (d, J=8Hz, 2H).

Step 2: Ketal 10 (1.31 g, 5.20 mmol) was dissolved in CH₃CN (50 mL) andCuCl₂.H₂O (0.890 g, 5.20 mmol) was added. The reaction mixture wasstirred at room temperature for 30 minutes. A second portion ofCuCl₂.H₂O (0.890 g, 5.20 mmol) was added, but no apparent change wasobserved by TLC. The reaction was filtered through a plug of silica gel(eluent 1:3 EtOAc:Hexanes) and the filtrate concentrated under reducedpressure. Purification by flash chromatography (silica gel, 1:9 to 1:4EtOAc:hexanes) gave 11 (330 mg, 30%): ¹H NMR (500 Mhz, CDCl₃) δ7.55-7.45 (m, 2H), 7.10-7.0 (m, 2H ), 2.95-2.85 (m, 4H), 2.4 -2.1 (m4H), 1.85 (s, 1H).

Step 3: Ketone 11 (0.330 g, 1.59 mmol), tyramine hydrochloride (0.275 g,1.59 mmol), and 3 Å molecular sieves were stirred in 2-propanol (10 mL,)for 2 hours. The reaction mixture was cooled in an ice bath, sodiumborohydride (0.075 g, 2.0 mmol) was added, and the mixture was stirredat room temperature overnight. The reaction was quenched with MeOH (3mL). After filtration through Celite, the solvent was removed underreduced pressure. Purification by chromatography (silica, 5:95 to 1:4MeOH:CH₂Cl₂) gave the free base (0.458 g, 87%) as a cis/trans mixture.Purification of the free base by chromatography (silica, 9:1 Et₂O:MeOH)gave the trans-isomertrans-4-{2-[4-(4-fluorophenyl)-4-hydroxycyclohexylamino]ethyl}phenol(163 mg, 30%): mp 84-89° C.; IR (KBr): 3500, 2933, 1509 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 7.51-7.46 (m, 2H), 7.06-6.96 (m, 4H), 6.73 (d,=8 Hz,2H), 2.90-2.85 (m, 2H), 2.75-2.61 (m, 3H), 1.90-1.39 (m, 8H); CI—MS(methane) (m/z): 330 [M+H]⁺; HPLC: method A, 7.76 minutes (93.5%);method B; 13.69 minutes (97.2%), Anal. Calcd for C₂₀H₂₄FNO₂.0.33H₂O:C,71.62; H, 7.41; N, 4.18. Found: C, 71.41; H, 7.42; N, 3.94.

EXAMPLE 4

Preparation oftrans-4-{3-[Methyl-(4-phenylcyclohexyl)amino]propyl}phenol

Step 1: To an ice-cold, stirred solution of 3-(4-hydroxyphenyl)propionicacid 7 (5.43 g, 32.7 mmol) in anhydrous THF (60 mL) was added BH₃—SMe₂(3.6 mL of a 1 M solution in THF, 3.6 mmol). The reaction was allowed towarm to room temperature overnight and then quenched with MeOH (100 mL).Concentration under reduced pressure gave alcohol 12 (4.96 g, 98%) as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 7.04 (d, J=8 Hz, 2H), 6.75 (d,J=8 Hz, 2H), 3.67 (m, 2H), 2.63 (t, J=7 Hz, 2H), 1.86 (m, 2H).

Step 2: A mixture of alcohol 12 (1.20 g, 7.74 mmol), K₂CO₃ (1.18 g, 8.52mmol), and benzyl bromide (1.10 mL, 9.29 mmol) in acetone (20 mL) washeated under reflux for 2 hours. The reaction mixture was cooled to roomtemperature, diluted with EtOAc (100 mL), and washed with H₂O andsaturated NaCl. The organic layer was dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification by flashchromatography (silica, 1:1 EtOAc:hexanes) gave alcohol 13 (1.15 g, 62%)as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.43-7.25 (m, 5H), 7.11 (d,J=6 Hz, 2H), 6.91 (d, J=6 Hz, 2H), 5.04 (s, 2H), 3.67 (dd, J=6 Hz, 2H),2.65 (t, J=6 Hz, 2H), 1.88 (m, 2H), 1.21 (t, J=6 Hz, 1H).

Step 3: To an ice-cold, stirred solution of alcohol 13 (0.440 mg, 1.83mmol) in CH₂Cl₂ (5 mL) was added Et₃N (0.22 g, 2.2 mmol) andmethanesulfonyl chloride (0.27 g, 2.38 mmol). After 20 minutes, thereaction mixture was poured into CH₂Cl₂ (150 mL) and washed successivelywith 2N HCl, H₂O, and saturated NaCl. After drying (Na₂SO₄),concentration under reduced pressure gave 14 (0.52 g, 86%), as a clearoil: ¹H NMR (500 MHz, CDCl₃) δ 7.44-7.35 (m, 5H), 7.08 (d, J=8 Hz, 2H),6.90 (d, J=8 Hz, 2H), 5.03 (s, 2H), 4.21 (t, J=6 Hz, 2H), 2.97 (s, 3H),2.74 (m, 2H), 2.08 (m, 2H).

Step 4: A mixture of mesylate 14 (0.50 g, 1.52 mmol), amine 6 (0.35 g,1.52 mmol), KI (0.28 g, 1.67 mmol), and NaHCO₃ (0.28 g, 3.33 mmol) inDMF (10 mL) was heated at 70° C. for 4 hours. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (200 mL), andthe organic layer was washed successively with H₂O and saturated NaCl.After drying (Na₂SO₄), concentration under reduced pressure gave 15(0.22 g, 69%), as a clear oil: ¹H NMR (500 MHz, DMSO-d₆) δ 7.44-7.21 (m,10H), 7.16 (d, J=8 Hz, 2H), 6.92 (d, J=8 Hz, 2H), 5.04 (s, 2H), 2.52 (m,6H), 2.51 (obs m, 1H), 2.47 (m, 1H), 2.23 (s, 3H), 1.98 (m, 4H), 1.45(m, 4H).

Step 5: A mixture of 15 (0.22 g, 0.53 mmol), 10% Pd/C (10% Pd/C), andHCl in ethanol (10 mL) was shaken under an atmosphere of H₂ at 50 psifor 3 hours. The mixture was filtered through Celite and the filtrateconcentrated under reduced pressure. Addition of 1:1 mixture of MeOH andEt₂O (2 mL) gave the HCl salt,4-{3-[methyl-(4-phenyl-cyclohexyl)amino]propyl}phenol (92 mg, 48%), as awhite solid: mp 249-255° C.; IR (KBr): 3164, 2942, 1613, 1516 cm⁻¹: ¹HNMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 7.29-7.18 (m, 5H), 7.03 (d, J=8Hz, 2H), 6.70 (d, J=8 Hz, 2H), 2.70 (m, 1H), 2.49 (m, 6H), 2.47 (s, 3H),2.08 (m, 1H), 1.95-1.89 (m, 4H), 1.59-1.39 (m, 4H); CI—MS (methane)(m/z): 324 [M+H]⁺; HPLC: method A, 6.48 minutes (98.0%); method B, 10.76minutes (97.3%); Anal. Calcd for C₂₂H₂₉NO.HCl.0.25H₂O: C, 72.51; H,8.44; N, 3.84. Found: C, 72.14; H, 8.06; N, 3.79.

EXAMPLE 5

Preparation of trans-4-[2-(4-Phenylcyclohexylamino)ethyl]phenol

To a stirred solution of tyramine (3.0 g, 22 mmol) in 2-propanol (100mL) and THF (50 mL) was added 4-phenylcyclohexanone 1 (3.8 g, 22 mmol)and 3 Å molecular sieves. After 2 hours, sodium borohydride (1.2 g, 31mmol) was added, and the reaction mixture was stirred overnight. Thereaction mixture was quenched with MeOH, filtered through Celite, andthe filtrate was concentrated under reduced pressure. Purification byflash chromatography (silica, 9:1 CH₂Cl₂:MeOH) gave the free base whichwas converted to an HCl salt. Recrystallization from MeOH/Et₂O gave thetrans-isomer trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (0.98 g,14%): mp 238-241° C.; IR (KBr): 2940, 1517, cm⁻¹; ¹H NMR (500 MHz,DMSO-d₆) δ 9.30 (s, 1H), 8.99 (br d, 1H), 7.30-7.15 (m, 5H), 7.07 (d,J=8 Hz, 2H), 6.73 (d, J=8 Hz, 2H), 3.10-3.07 (m, 3H), 2.89-2.86 (m, 2H),2.53-2.50 (m, 1H), 2.20 (d, J=20 Hz, 2H), 1.88 (d, J=20 Hz, 2H),1.59-1.46 (m, 4H); CI—MS (methane) (m/z): 296 [M+H]⁺; HRMS-API (m/z):[M+H]⁺ calcd for C₂₀H₂₅NO, 296.2014; found, 296.2015; HPLC: method A,5.83 minutes (100%); method B, 10.56 minutes (96.5%); Analysis Calcd forC₂₀H₂₅NO.HCl.0.25H₂O: C, 71.41; H, 7.94; N, 4.16. Found: C, 71.29; H,7.66; N, 4.12.

EXAMPLE 6

Preparation of trans 4-{2-[Methyl(4-phenylcyclohexyl)amino]ethyl}phenol

To a stirred solution oftrans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (380 mg, 1.3 mmol) inMeOH (5 mL), H₂O (0.5 mL), and CH₂Cl₂ (5 mL) was added ρformaldehyde(200 mg, 6.5 mmol). After stirring for 15 minutes NaBH(OAc)₃ (340 mg,1.6 mmol) was added, and the reaction mixture was stirred for 12 hours.Additional NaBH(OAc)₃ (138 mg, 0.65 mmol) was added, and the mixture wasstirred for 2 days. NaBH(OAc)₃ (138 mg, 0.65 mmol) was added, andstirring was continued for 6 hours. Solid NaOH was added to give a clearsolution, which was concentrated under reduced pressure. Purification byflash chromatography (silica, 89:10:1 CH₂Cl₂:MeOH:NH₄OH) and formationof the HCl salt gavetrans-4-{2-[methyl(4-phenylcyclohexyl)amino]ethyl}phenol (380 mg, 64%),as an off-white solid: mp 97-105° C.; IR (KBr): 2941, 1614, 1517 cm⁻¹;¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.42 (s, 1H), 7.35-7.15 (m,5H), 7.10 (br d, J=8 Hz, 2H), 6.77 (br d, J=8 Hz, 2H), 3.49-2.94 (m,6H), 2.80-2.70 (m, 2H), 2.56-2.48 (m, 1H), 2.30-2.11 (m, 2H), 1.89 (brd, J=11.5 Hz, 2H), 1.75-1.50 (m, 4H); CI—MS (methane) (m/z): 310 [M+H]⁺;HPLC: method A, 5.99 minutes (99.4%); method B, 10.68 minutes (99.1%);Anal. Calcd for C₂₁H₂₇NO.HCl.0.25H₂O: C, 71.98; H, 8.20; N, 4.00. Found:C, 71.60; H, 8.31; N, 3.86.

EXAMPLE 7

(a) trans-4-[4-(4-Phenyl-cyclohexylamino)butyl]phenol

(b) trans-4-{4-[Methyl(4-phenylcyclohexyl)amino]butyl}phenol

Step 1: To an ice-cold, stirred solution of alcohol 16 (1.5 g, 8.3 mmol)in TBF (40 mL), under an N₂ atmosphere, was added Et₃N (1.7 mL, 12 mmol)followed by methanesulfonyl chloride (0.77 mL, 10 mmol). After 1 hour,the reaction mixture was partitioned between EtOAc and 1N HCl. Theorganic layer was washed with H₂O, saturated NaHCO₃, saturated NaCl,dried (Na₂SO₄), and filtered. Concentration under reduced pressure gavemesylate 17 (2.2 g, 100%), which was used without further purification:¹H NMR (300 MHz, CD₃OD) δ 7.10 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.5 Hz,2H), 4.25-4.20 (m, 2H), 3.75 (s, 3H), 3.03 (s, 3H), 2.62-2.56 (m, 2H),1.73-1.40 (m, 4H).

Step 2: A mixture of 17 (1.2 g, 4.6 mmol), NaHCO₃ (0.86 g, 10 mmol), KBr(0.61 g, 5.1 mmol), and amine 5 (0.80 g, 4.6 mmol) in DMF (45 mL) washeated at reflux for 6 hours and then cooled to room temperature. Themixture was diluted with EtOAc and washed with H₂O, saturated NaCl,dried (Na₂SO₄), and filtered. Concentration under reduced pressurefollowed by flash chromatography (silica, 95:5 CH₂Cl₂:MeOH) andformation of the HCl salt gave compound 18 (0.85 g, 77%): ¹H NMR (300MHz, CD₃OD) δ 7.30-7.10 (m, 7H), 6.88-6.81 (m, 2H), 3.75 (s, 3H),3.20-3.00 (m, 3H), 2.70-2.51 (m, 3H), 2.27-2.19 (m, 2H), 2.06-1.98 (m,2H), 1.80-1.45 (m, 8H).

Step 3: To an ice-cold, stirred solution of compound 18 (0.75 g, 2.2mmol) in CH₂Cl₂ (10 mL) was added a solution of BBr₃ (0.38 mL, 4.0 mmol)in CH₂Cl₂ (5 mL) over 5 minutes After 1 hour, the reaction mixture waspoured into ice-cold saturated NaHCO₃ and extracted with CH₂Cl₂.Concentration under reduced pressure, followed by flash chromatography(silica, 89:10:1 CH₂Cl₂:MeOH:NH₄OH), gave4-[4-(4-phenylcyclohexylamino)-butyl]-phenol (285 mg, 44%), as a whitesolid: mp 160-164° C.; IR (KBr): 2934, 1613, 1515 cm⁻¹; ¹H NMR (500 MHz,DMSO-d₆) δ 9.03 (s, 1H), 7.27-7.13 (m, 5H), 6.96 (d, J=8 Hz, 2H), 6.65(d, J=8 Hz, 2H), 2.58-2.34 (m, 5H), 1.98-1.92 (m, 2H), 1.80-1.75 (m,2H), 1.58-1.34 (m, 6H), 1.30-1.23 (m, 1H), 1.15-1.06 (m, 2H); CI—MS(methane) (m/z): 324 [M+H]⁺; HRMS-API (m/z): [M+H]⁺ calcd for C₂₂H₂₉NO,324.2327; found, 324.2324; HPLC: method A, 6.28 minutes (>99%); methodB, 11.44 minutes (>99%); Anal Calcd for C₂₂H₂₉NO.0.25H₂O: C, 80.57; H,9.07; N, 4.27. Found: C, 80.69; H, 8.89; N, 4.22.

Step 4: To a stirred solution oftrans-4-[4-(4-phenylcyclohexylamino)-butyl]phenol (370 mg, 1.1 mmol) ina mixture of MeOH (5 mL) H₂O (0.5 mL), and CH₂Cl₂ (5 mL) was addedρformaldehyde (170 mg, 5.7 mmol). After stirring for 10 minutes,NaBH(OAc)₃ (300 mg, 1.4 mmol) was added, and the reaction mixture wasstirred for 12 hours. Solid NaOH was added to give a clear solution,which was then concentrated under reduced pressure. Purification byflash chromatography (silica, 89:10:1 CH₂Cl₂:MeOH:NH₄OH) and formationof the HCl salt gave (b)trans-4-{4-[methyl-(4-phenylcyclohexyl)amino]butyl}-phenol (230 mg,56%), as a white solid: mp 234-236° C.; IR (KBr): 2942, 1613, 1515 cm⁻¹;¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br s, 1H), 9.13 (s, 1H), 7.31-7.18 (m,5H), 7.00 (d, J=8.5 Hz, 2H), 6.68(d, J=8.5 Hz, 2H), 3.33-3.23 (m, 1H),3.17-3.09 (m, 1H), 3.02-2.95 (m, 1H), 2.67(d, J=5 Hz, 3H), 2.55-2.49 (m,3H), 2.16-2.06 (m, 2H), 1.95-1.89 (m, 2H), 1.72-1.50 (m, 8H); CI—MS(methane) (m/z): 338 [M+H]⁺; HPLC: method A, 6.38 minutes (>99%); methodB, 11.28 minutes (>99%); Anal. Calcd for C₂₃H₃₁NO.HCl: C, 73.87; H,8.62; N, 3.75. Found: C, 73.61; H, 8.55; N, 3.66.

Electrophysiological Assays at NMDA Receptor Subunits

Preparation of RNA. cDNA clones encoding the NR1A, NR2A, NR2B, and NR₂Crat NMDA receptor subtypes were used. (See Moriyoshi et al., Nature,(Lond.), 1991;354:31-37); Kutsuwada et al., Nature (Lond.),1992;358:36-41; Monyer et al., Science (Washington, D.C.),1992;256:1217-1221; Ikeda et al., FEBS Lett., 1992;313:34-38; Ishii etal., J. Biol. Chem., 1993;268:2836-2843 for details of these clones ortheir mouse homologs.) The clones were transformed into appropriate hostbacteria, and plasmid preparations were made with conventional DNApurification techniques. A sample of each clone was linearized byrestriction enzyme digestion of cRNA was synthesized with T3 RNApolymerase. The cRNA was diluted to 400 ng/μL and stored in 1-μLaliquots at −80° C. until injection.

The Xenopus Oocyte Expression System. Mature female Xenopus laevis, wereanaesthetized (20-40 minutes) using 0.15% 3-aminobenzoic acid ethylester (MS-222); and 2 to 4 ovarian lobes were surgically removed.Oocytes at developmental Stages IV-VI (Dumont J. N., J. Morphol.,1972;136:153-180) were dissected from the ovary still surrounded byenveloping ovarian tissues. Follicle-enclosed oocytes weremicro-injected with 1:1 mixtures of NR1A:NR2A, 2B or 2C; injecting 1 ngto 10 ng of RNA encoding each receptor subunit. NR1A encoding RNA wasinjected alone at ˜20 ng. Oocytes were stored in Barth's mediumcontaining (in mM): NaCl, 88; KCl, 1; CaCl₂, 0.41; Ca (NO₃)₂, 0.33;MgSO₄, 0.82 NaHCO₃, 2.4; HEPES 5, pH 7.4, with 0.11 mg/mL gentamicinsulphate. While oocytes were still surrounded by enveloping ovariantissues, the Barth's medium was supplemented with 0.1% bovine serum.Oocytes were defolliculated 1 to 2 days following injections bytreatment with collagenase (0.5 mg/mL Sigma Type I for 0.5-1 hr) (Milediand Woodward, J. Phsyiol. (Lond.), 1989;416:601-621) and subsequentlystored in serum-free medium.

Electrical recordings were made using a conventional two-electrodevoltage clamp (Dagan TEV-200) over periods ranging between 3 to 21 daysfollowing injection (Woodward et al., Mol. Pharmacol., 1992;41:89-103).Oocytes were placed in a 0.1 mL recording chamber continuously perfused(5-15 mL min⁻¹) with frog Ringer's solution containing (in mM): NaCl,115; KCL, 2; BaCl₂, 1.8; HEPES, 5; pH 7.4. Drugs were applied by bathperfusion. Using oocytes expressing different subunit combinations ofNMDA receptor, NMDA currents were activated by co-application ofglutamate (100 μM) and glycine (1-100 μM). Inhibitory potency of thenovel antagonists was assessed on responses elicited by fixedconcentrations of glutamate and glycine, by measuring reductions incurrent induced by progressively increasing concentrations ofantagonist.

Concentration-inhibition curves were fit with Equation 1.

I/I _(control)=1/(1+([antagonist]/10^(−pIC) ^(₅₀) )^(n))  Eq.1

In which I_(control) is the current evoked by agonists alone, pIC₅₀=−logIC₅₀, IC₅₀ is the concentration of antagonist that produced half maximalinhibition, and n is the slope factor (De Lean et al., Am. J. Physiol.,1978;235:E97-102). For incomplete curves, analysis by fitting wasunreliable, and IC₅₀ values were calculated by simple regression overlinear portions of the curves (Origin: Microcal Software). Theelectrophysiological assay results are set forth in Table 1.

6-OHDA Lesioned Rat Assay

6-Hydroxydopamine-lesioned rats were used (see Ungerstedt, U.,Arbuthnott, G. W., Quantitative recording of rotational behavior in ratsafter 6-hydroxy-dopamine lesions of the nigrostraiatal dopamine system.Brain Res., 1971;24(3):485-93). Adult male Sprague-Dawley rats wereanesthetized with chloral hydrate, and unilateral lesions of thenigrostriatal dopamine system were accomplished by infusion of 8 μg of6-hydroxydopamine HBr (6-OHDA) into the right medial forebrain bundle.Rats were pretreated 30 minutes before surgery with desipramine HCl 25mg/kg intraperitoneally (IP) to protect noradrenegic neurons, andpargyline 25 mg/kg IP to potentiate the effects of 6-OHDA. A minimum of3 weeks after surgery, the rotational behavior induced by apomorphineHCL 50 μg/kg subcutaneously (SC) was assessed. Only rats demonstratingmore than 100 contraversive turns/hour to apomorphine were used for thepresent experiments.

Rotational behavior was measured using an automatic rotometer system(Rotorat Rotational Activity System, MED Associates, Georgia, Vt.).Antiparkinsonian activity was assessed as the ability of the compound topotentiate the contraversive rotation induced by L-DOPA methyl ester, 10mg/kg SC, over a 6-hour period. Experiments were conducted using acrossover paradigm where each rat received either a vehicle plus L-DOPA,or the test compound plus L-DOPA, in randomized order. Rats were testedat 7-day intervals. In experiments in which the compound was testedorally, rats were food deprived for 16 hours. Statistical analysisbetween treatment groups were performed using a paired t-test. Theresults were reported in Table 1 as the minimum effective dose (MED) ofcompound (mg/kg) required to produce a statistically-significantincrease in total contraversive rotations compared to rats receivingL-DOPA only.

[³H]Ifenprodil Binding Assay Protocol

Materials and Methods

All buffers and reagents used in assay incubations or to dissolve drugswere prepared using water purified through a Milli-Q reverse osmosissystem (Millipore Corp, Bedford, Mass.) and treated with UV emissions.Prior to use in the assays, buffers were further filtered through asterile Corning filtration unit (Corning Glass Works, Corning, N.Y.)containing a 0.2-μm filter. Buffer used to rinse the membranes on theassay filters was prepared with purified water, but was not refilteredand was stored no longer than 5 days. Stock solutions of the drugs(usually 10 mM) were dissolved in 20 mM HEPES-KOH buffer pH 7.4 (assaybuffer) with the addition of 1 to 5 μL of glacial AcOH, if needed, tokeep them in solution. For eliprodil the stock solution was buffer withthe addition of 10% DMSO. All subsequent dilutions from stock were madein buffer.

Membrane Preparation

An extensively washed buffy coat membrane fraction was prepared fromfrozen adult rat forebrains (Zivic-Miller Laboratories, Inc, Zelienople,Pa.) as described previously (Coughenour L. L.; Cordon, J. J., J.Pharmacol. Exp. Ther., 1997;280:584-592) and stored at −80° C. On theday of the assay, pellets were resuspended in 35 mL of assay buffer atpH 7.4 using a Polytron setting 6. After incubation at 37° C. for 30minutes in a shaking water bath, the homogenate was centrifuged 40,000×gfor 10 minutes at 4° C. The pellets were resuspended in fresh buffer andcentrifuged 3 more times before final suspension for use in the assay.

Binding Studies

[³H]Ifenprodil Binding. Triplicate incubations were carried out in avolume of 0.5 mL in 1.3 mL polypropylene tubes (Marsh BiomedicalProducts Inc, Rochester, N.Y.) for 2 hours at room temperature.Incubations contained test agents, membranes (100-200 μg protein) and 4nM [³H]-ifenprodil in 20 mM HEPES-KOH buffer, pH 7.4 (assay buffer).Assays were started by addition of the membranes. Bound radioligand wasseparated by filtration under reduced pressure using a Tomtec Mach II,96-well cell harvester (Tomtec Inc, Orange, Colo.). Filtration wasthrough Whatman GF/B glass fiber filters (Whatman Ltd, Maidstone,England), which had been soaked for at least 15 minutes in 0.3%polyethylenimine and allowed to air dry. The filters were rinsed with 3mL of ice-cold assay buffer within 6 seconds. Air was allowed to passthrough the filters for an additional 10 seconds to remove residualmoisture. The filter mat was supported on a cold (−20° C.) teflonsupport, and filters from individual wells were separated and placed inMini Poly-Q vials (Beckman Instruments Inc, Fullerton, Calif.) andfilled with 4 mL of scintillation cocktail (Beckman Ready Protein⁺).Radioactivity retained on the filter was determined by liquidscintillation spectrophotometry. Nonspecific binding was defined as thebinding in the presence of 1 mM ifenprodil. Specific binding was 90%.

[³H]-TCP Binding. Binding assays were carried out essentially asdescribed for [³H]ifenprodil binding. Incubations contained test agents,100 μg to 200 μg protein, 2 nM [³H]TCP and 10 μM glutamate, glycine, andspermidine. Incubations were for 10 m to allow assays to be carried outunder nonequilibrium conditions for the detection of binding selectiveto NMDA receptors of the NR2B subtype. Specific binding was defined asthe binding displaced by 100 μM (+)MK-801 and was 90% of the totalbinding.

Data Analysis. Binding curves were statistically analyzed for a bestone- or two-site competition fit using GraphPad Prism software (GraphPadSoftware Inc, San Diego, Calif.). The normalized data was fit bynonweighted nonlinear regression to either${y = {{Bottom} + {\frac{( {{Top} - {Bottom}} )}{1 + {10^{x - {\log \quad {EC}}}50}}\quad {or}}}}\quad$$y = {{Bottom} + {( {{Top} - {Bottom}} )\frac{{Fraction} - 1}{1 + {10^{x - {\log \quad {EC}}}50^{- 1}}}} + {\frac{1 - {Fraction} - 1}{1 + {10^{x - {\log \quad {EC}}}50^{- 2}}}.}}$

Control data was entered as 100%, and no parameters were constrained.Inhibition curves were compared by ANOVA with posttest comparisons ofthe log IC₅₀ using Dunnett's multiple comparisons posttest or Student'snonpaired, two-tailed t-test (GraphPad InStat software).

Materials:

TCP, [piperidyl-3,4⁻³H(N)]-(specific activity, 45 to 50 Ci/mmol) andifenprodil, [phenyl-³H]-(specific activity, 66.2 Ci/mmol) were purchasedfrom Dupont NEN Research Products (Boston, Mass.). Ifenprodil tartrate,trifluperidol hydrochloride, and GBR-12909 dihydrochiloride werepurchased from Research Biochemicals International (Natick, Mass.).Spermidine trihydrochloride was purchased from United States BiochemicalCorp (Cleveland, Ohio). HEPES, glutamate, and glycine were purchasedfrom Sigma Chemical Co (St. Louis, Mo.). Haloperidol was obtained fromMcNeil Laboratories (Raritan, N.J.) or Research BiochemicalsInternational. Eliprodil was synthesized by Thomas Malone (Parke-DavisPharmaceutical Research, Ann Arbor, Mich.), and (+)MK-801 wassynthesized by Leonard Lescosky (Parke-Davis Pharmaceutical Research,Ann Arbor, Mich.).

TABLE 1 NR1A/NR2B [³H]Ifenprodil Example Oocyte IC₅₀ (μM) IC₅₀ (μM) 1b0.084 2b 0.15 0.045 2a 1.295

While the forms of the invention exemplified herein such as, forexample, the named species of Formulas I-III and the recitation oftreatment of Parkinson's constitute presently preferred embodiments,many others are possible. It is not intended that said recited speciesof Formulas I-III and preferred methods of use should, in any manner,limit or restrict the invention from the full scope claimed herein. Itis not intended herein to name all of the possible equivalent forms orramifications of the invention. It is understood that the terms usedherein are merely descriptive, rather than limiting. For example, theterm “Parkinson's disease” is merely descriptive, and not limiting, ofthe term “neurodegenerative disease.”

What is claimed is:
 1. A compound of Formula I or a pharmaceuticallyacceptable salt thereof:

wherein: Ar is unsubstituted or substituted phenyl, the substituents areselected from the group F, Cl, Br, I, CN, NO₂, OCH₃, OC(O)CH₃, CF₃,OCH₂CH₂OH or N(CH₃)₂; E is hydrogen;

wherein m is an integer of from 1 to 3; R is hydrogen, methyl,H₂NC(O)alkyl, alkenylalkyl, heteroaralkyl, (C₃-C₇ cycloalkyl)alkyl, orC(O)CH₃; Y is OH; X is hydrogen; and * denotes trans.
 2. A compoundaccording to claim 1 selected from:trans-4-[3-(4Phenylcyclohexylamino)propyl]phenol;trans-4-[(1S,2S)-1-Hydroxy-2(4-phenylcyclohexylamino)prophyl]phenol;trans-4-{2[4-(4-Flurophenyl)-4-hydroxycyclohexylamino]ethyl}phenol;trans-4-{3[Methyl(4-phenylcyclohexy)amino]prophyl}phenol;trans-4-[(4Phenylcyclohexylamino)ethyl]phenoltrans-4-{2[Methyl(4phenylcyclohexyl)amino]ethyl}phenol;trans-4-[4-(4Phenylcyclohexylamino)butyl]phenol; andtrans-4-{4-[Methyl(4-phenylcycloheyl)amino]butyl}phenol.
 3. Apharmaceutical composition useful for treating disorders responsive tothe selective blockade of N-menthyl-D-aspartate receptor subtypes in amammal, including a human, optionally disorders as stroke, cerebralischemia, trauma, hypoglycemia, neurodegenerative disorders, anxiety,depression, migraine headache, convulsions, aminoglycosideantibiotics-induced hearing loss, psychosis, glaucoma, CMV retinitis,opioid tolerance or withdrawal, chronic pain, or urinary incontinencethe compositions comprising a pharmaceutically acceptable carrier,excipient, or diluent and a therapeutically effective amount of at leastone compound of claim
 1. 4. The pharmaceutical composition according toclaim 3, wherein the neurodegenerative disorder is Parkinson's disease.5. A method for treating disorders responsive to the selective blockadeof N-metbyl-D-aspartate receptor subtypes in a mammal, including ahuman, suffering therefrom which comprises administering in unit dosageform at least one compound represented by Formula I of claim
 1. 6. Themethod according to claim 5, wherein the disorder is Parkinson'sdisease.
 7. The method according to claim 6, further comprisingadministering in unit dosage form a compound of Formula I to a mammalsuffering from Parkinson's disease.